Zonation of the drug-metabolizing enzyme cytochrome P450 3A in infant mice begins in pre-weaning period

Kitaoka, Satoshi; Hatogai, Jo; Ochiai, Wataru; Sugiyama, Kiyoshi

doi:10.2131/jts.43.223

Cited by 7 publications

(7 citation statements)

References 11 publications

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“…For instance, necrosis causing cell mass loss may be responsible for the decrease of P450 expression. In AILI, necrosis mainly happened around a central vein area of the liver, where P450s are primarily expressed (Kietzmann, 2017;Kitaoka et al, 2018). Further immunostaining experiment may be required to test the zonation changes of P450s with APAP treatment.…”

Section: Discussionmentioning

confidence: 99%

Acetaminophen-Induced Liver Injury Alters Expression and Activities of Cytochrome P450 Enzymes in an Age-Dependent Manner in Mouse Liver

et al. 2020

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Drug-induced liver injury (DILI) is a global medical problem. The risk of DILI is often related to expression and activities of drugmetabolizing enzymes, especially cytochrome P450s (P450s). However, changes on expression and activities of P450s after DILI have not been determined. The aim of this study is to fill this knowledge gap. Acetaminophen (APAP) was used as a model drug to induce DILI in C57BL/6J mice at different ages of days 10 (infant), 22 (child), and 60 (adult). DILI was assessed by levels of alanine aminotransferase and aspartate aminotransferase in plasma with a confirmation by H&E staining on liver tissue sections. The expression of selected P450s at mRNA and protein levels was measured by real-time polymerase chain reaction and liquid chromatography-tandem mass spectrometry, respectively. The activities of these P450s were determined by the formation of metabolites from probe drugs for each P450 using ultraperformance liquid chromatography-quadrupole time of flight mass spectrometry. DILI was induced at mild to severe levels in a dose-dependent manner in 200, 300, and 400 mg/kg APAP-treated groups at child and adult ages, but not at the infant age. Significantly decreased expression at mRNA and protein levels as well as enzymatic activities of CYP2E1, 3A11, 1A2, and 2C29 were found at child and adult ages. Adult male mice were more susceptible to APAP-induced liver injury than female mice with more decreased expression of P450s. These results suggest that altered levels of P450s in livers severely injured by drugs may affect the therapeutic efficacy of drugs, which are metabolized by P450s, more particularly for males. SIGNIFICANCE STATEMENTThe current study in an animal model demonstrates that acetaminophen-induced liver injury results in decreased expression and enzyme activities of several examined drug-metabolizing cytochrome P450s (P450s). The extent of such decreases is correlated to the degree of liver injury severity. The generated data may be translated to human health for patients who have drug-induced liver injury with decreased capability to metabolize drugs by certain P450s.

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Section: Discussionmentioning

confidence: 99%

Acetaminophen-Induced Liver Injury Alters Expression and Activities of Cytochrome P450 Enzymes in an Age-Dependent Manner in Mouse Liver

et al. 2020

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“…The CBD levels of the fetal brain were similar to those of other organs. We also report that the CYP3A family involved in CBD metabolism is rarely expressed in the fetal liver during this period (Ochiai et al, 2016;Kitaoka et al, 2018a;Kitaoka et al, 2018b). Therefore, we felt the need to measure CBD levels in the liver.…”

Section: Discussionmentioning

confidence: 99%

“…Concerning metabolism, CBD is oxidized in the adult liver by cytochrome P450 (CYP) 3A at the 6β, 2′, and 4′ positions (Jiang et al, 2011;Ujvary and Hanus, 2016). However, the metabolic activity of CYP3A is significantly lower in the fetal liver than in the adult liver (Ochiai et al, 2016;Kitaoka et al, 2018a;Kitaoka et al, 2018b). Therefore, it is considered that CBD is distributed throughout the entire fetal body with little metabolism in the liver.…”

Section: Introductionmentioning

confidence: 99%

Maternal and Fetal Pharmacokinetic Analysis of Cannabidiol during Pregnancy in Mice

et al. 2021

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Cannabidiol (CBD), a major component of cannabis, has various effects such as antiemetic and anxiolytic activities, and it has recently been marketed as a supplement.The number of people using CBD during pregnancy is increasing, and there are concerns about its effects on the fetus. In addition, the scientific evidence supporting the fetal safety of CBD use during pregnancy is insufficient. To investigate CBD transfer from the mother to the fetus, a single intravenous dose of CBD was administered to pregnant mice in this study, and fetal pharmacokinetics (distribution and elimination) was analyzed. The transfer of CBD from the maternal blood to the fetus was rapid, and the compound accumulated in the fetal brain, liver, and gastrointestinal tract.Conversely, little CBD was transferred from the mother to the amniotic fluid. We analyzed the pharmacokinetics of CBD using a two-compartment model and found that the maternal and fetal half-lives of CBD were approximately 5 and 2 h, respectively. Furthermore, we performed a moment analysis of the pharmacokinetics of CBD, observing a mean residence time of less than 2 h in both the mother and fetus. These results suggest that once-daily CBD intake during pregnancy is unlikely to result in CBD accumulation in the mother or fetus.

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“…In the adult liver, many drug‐metabolizing enzymes, including CYPs, are strongly expressed around the central vein (CV) and rarely around the portal vein. This characteristic expression pattern is called zonation structure and contributes to the efficient metabolism of drugs (Annunziato & Tchorz, 2021; Kitaoka, Hatogai, Ochiai, & Sugiyama, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…Thus, although many studies have been reported on CYPs in the liver, they have focused only on the expression levels of CYPs, and there is little information on their relationship to zonation formation, which affects metabolic efficiency (Kitaoka, Hatogai, Iimura, et al., 2018; Kitaoka, Hatogai, Ochiai, et al., 2018).…”

Section: Introductionmentioning

confidence: 99%

Mouse Cyp2c expression and zonation structure in the liver begins in the early neonatal stage

Kawamura

Ichikawa

Hatogai

et al. 2022

Biopharm & Drug Disp

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In the adult liver, drug-metabolizing enzymes such as cytochrome P450 (CYP) efficiently metabolize drugs by forming an expression pattern called "zonation" structure around the central veins (CV). However, most previous studies on CYPs have focused on the expression levels of CYP mRNA and proteins in the whole liver.In this study, we analyzed not only the expression levels of Cyp2c family mRNAs and proteins in mice during fetal liver development, but also the relationship with their localization. In the whole fetal liver, Cyp2c mRNA and protein were hardly expressed. On the other hand, zonation analysis results showed that only some cells around the CV of the fetal liver expressed Cyp2c. In addition, the protein expression level of Cyp2c in the whole liver during the neonatal period started from postnatal day (P) 7 in both males and females, while the zonation was weakly formed from P5.This study suggested that fetal liver cannot metabolize Cyp2c substrate drugs transferred from mother to fetus due to the low expression of Cyp2c and unformed zonation. The expression level of Cyp2c protein in neonates was lower than that in adult liver, and the zonation structure was not clear, suggesting that drug metabolism was not sufficient. Furthermore, this study revealed that the expression level of Cyp2c does not correlate with the formation of zonation structures, because Cyp2c expression is found in hepatocytes near the CV even in the fetal and neonatal stages, when Cyp2c protein expression is hardly detectable in the whole liver.

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Zonation of the drug-metabolizing enzyme cytochrome P450 3A in infant mice begins in pre-weaning period

Cited by 7 publications

References 11 publications

Acetaminophen-Induced Liver Injury Alters Expression and Activities of Cytochrome P450 Enzymes in an Age-Dependent Manner in Mouse Liver

Acetaminophen-Induced Liver Injury Alters Expression and Activities of Cytochrome P450 Enzymes in an Age-Dependent Manner in Mouse Liver

Maternal and Fetal Pharmacokinetic Analysis of Cannabidiol during Pregnancy in Mice

Mouse Cyp2c expression and zonation structure in the liver begins in the early neonatal stage

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